Models for direct activation of BM-resident or circulating HSPCs by PAMPs. (A) Steady-state hematopoiesis ensures homeostatic proliferation and differentiation of different hematopoietic lineages (left). In settings of systemic infection, PAMPs are elevated in circulation and reach the BM, where they directly act on TLR-expressing HSPCs and instruct enhanced generation of a lineage at demand (right). (B) Under steady-state conditions TLR-expressing HSPCs constantly leave the BM (1), enter systemic circulation, perambulate peripheral tissues and some re-home to the BM (2). On the encounter of invading pathogens in peripheral tissues (3), pathogen-mediated triggering of TLRs on HSPCs induces migration arrest (4) and promotes HSPC proliferation and differentiation to ensure local supply of myeloid effector cells (5). (C) In steady state, the majority of blood cell lineages develop in the BM (1) with mostly mature cells leaving (2) to eventually enter their destination tissues where they exert their effector functions. During the course of a systemic immune response when certain lineages are in high demand at specific sites, TLR ligation on lineage-committed progenitors in the BM (3) causes mobilization from the BM and recruitment to these sites (eg, lymph nodes; 4), where they proliferate and differentiate in response to local pathogen (5) to replenish consumed immune effector cells (6).